Mutations in the genes encoding presenilins 1 and 2 (PS-1 and PS-2) and the beta-amyloid precursor protein (APP) are the leading cause of familial, early-onset Alzheimer's disease (FAD). Over-expression of these gene mutations in transgenic mice recapitulates pathological and behavioral features of AD. It has supported the hypothesis that aggregation of the amyloid Abeta 42 protein is an important trigger for disease onset and progression, and fostered the development of therapeutic strategies based on reducing Abeta deposition. However, the utility of transgenic models for investigating AD pathogenesis and evaluating candidate therapies is constrained by the dependence on ectopic over-expression. As an alternative, we introduced mouse experimental models in which gene targeting was used to "knock-in" disease-causing mutations into their endogenous genes. Our studies established the only mouse model for AD-type amyloid and tau neuropathologies that does not rely on over-expression, and identified neurobiological and molecular mechanisms central to AD pathogenesis. The proposed research would extend these findings by delineating at the molecular level a key mechanism for Abeta42 overproduction, defining the role for amyloid and tau pathologies in impairing forms of adaptive plasticity in neural systems known to be both important for long- term memory and severely impacted in AD, and identifying therapies that reverse these pathologies and rescue the plasticity deficits. Specific Aim 1 will identify structural and functional changes caused by mutant PS-1 in the mouse brain gamma-secretase, the protease that forms the amyloid Abeta 42 protein, and test the hypothesis that mutant PS-1 confers a pathogenic conformation on the protease. Specific Aim 2 will test the hypothesis that the amyloid and tau pathologies impair synaptic plasticity in the perforant pathway, and evaluate two pharmacologic strategies for reversing these defects. Specific Aim 3 will test the hypothesis that mutant PS-1 impairs neurogenesis in the adult hippocampus through amyloid-mediated neuroinflammation, and determine its pharmacologic reversibility. The proposed research will advance our understanding of pathogenic mechanisms of FAD-linked gene mutations and evaluate therapeutic strategies aimed at slowing the onset and progression in a faithful mouse genetic model of FAD. [unreadable] [unreadable] [unreadable]